In the following paragraphs protein drugs will be discussed as typical examples of drug molecules that are either large molecules or highly susceptible to enzyme degradation. However, additional non-proteinous drugs can be included in this group and they will be discussed later.
Medical use of protein drugs is constrained by three major drawbacks. The first is their short biological half-life which requires, in some cases, frequent administrations. The second is the rapid degradation which occurs in mucosal tissues that generally cover the body cavities. Lastly, most protein drugs are large molecules and therefore do not easily cross the intestinal epithelium. Therefore, the most common mode of protein drugs administration is the parenteral route. However, apart from the inconvenience to the patients, parenteral delivery systems are also more expensive in terms of production and drug administration. There is therefore a need for an effective non-parenteral mode of administration of protein drugs that will provide protection against biological degradation and/or enhance its transport across mucosal barriers. Although sophisticated non-parenteral pharmaceutical systems, such as intra-nasal systems, have been developed, oral administration is more favorable, having the major advantage of convenience for increased patient compliance. Sometimes oral administration of peptides offers physiological advantages, for example oral administration of insulin is superior to parenteral administration because, like the native hormone secreted by the pancreas, it also drains primarily into the portal vein to exert its initial effect on the liver. Some insulin will then find its way into the peripheral circulation via lymphatic channels [Goriya, Y., et al., Diabetologia 19:454–457 (1980)]. In contrast, injected insulin is drained entirely into the peripheral circulation and has access to all parts of the body. Notwithstanding these advantages, most protein drugs have not been orally delivered to date because of the lack of a simple and reliable drug delivery system that will be able to overcome the biological and physico-chemical constraints mentioned above.
An effective oral carrier for protein drugs should (a) shield its content against the luminal and brush border peptidases and (b) be capable of facilitating the uptake of the protein drug—usually a large molecular weight entity—across the gastrointestinal (GI) epithelium. Many studies have reported that protein drugs such as insulin, vasopressin, calcitonin, enkaphalins and thyrotropin-releasing hormone (TRH) were administered relatively successfully via the oral route [Lee, V. H. L., et al., Oral Route of Peptide and Protein Drug Delivery, in V. H. L. Lee (Ed.): Peptide and Protein Drug Delivery, Marcel Dekker, 1991 New York, pp 691–738]. An increase in the bioavailability of protein drugs after oral administration can be accomplished by the co-administration of either peptidases inhibitors, to help keep the protein drug as intact as possible at the site of absorption, or of protein absorption enhancers. Some works report the use of both absorption enhancers and peptidase inhibitors in the same formulation [e.g. Ziv, E., et al., Biochem. Pharmcol. 36:1035–1039 (1987)]. Some typical examples of oral administration of the protein drug insulin together with peptidase inhibitors or absorption enhancers are listed below.
Morishita et al. [Int. J. Pharm. 78:1–7 (1992)] found that after formulating insulin together with protease inhibitors such as trypsin inhibitor, chemostatin, Bowman-Birk inhibitor and aprotinin into Eudragit L-100R microspheres, the insulin was resistant to pepsin, trypsin and α-chymotrypsin in vitro. However, in similar experiments performed in vivo by Laskowski and coworkers in which insulin was injected together with soybean trypsin inhibitor (SBTI) or, alternatively, without any inhibitor, a very small pharmacodynamic response was observed [Laskowski, M., Jr., et al., Science 127:1115–1116 (1958)]. Similar results were observed by Danforth and coworkers who also found that diisopropylfluorophosphate was an effective depressant of insulin digestion, while SBTI was not [Danforth, E., et al., Endocrinology 65:118–123 (1959)]. In contrast, it was found that the addition of SBTI solution boosted the pharmacological effect of insulin, namely reduction of blood glucose level, after its injection into the lumen of rat ileum [Kidron, M., et al., Life Sci. 31:2837–2841 (1982)]. Takahashi et al. used decanoic acid to enhance the absorption of the hydrophilic non-absorbable marker phenol sulfon phthalate. They found that the absorption correlated to the rate of disappearance of the decanoic acid from the intestine. The absorption onset was within few minutes. This indicates that there is a rationale to apply an absorption enhancer for improved functioning of the delivery system.
Table A and Table B hereunder itemize some examples of absorption enhancers and protease inhibitors reported in the literature.
TABLE AClasses of enhancers tested to promote drug absorption in the GItract and some of their representatives(References listed after Table A)CLASSEXAMPLESNSAID (non-steroidalSodium salicylateantiinflammatory drugs)Sodium 5-methoxysalicylateand derivativesIndomethacinDiclofenacSurfactantsNonionic: polyoxyethylene ethersAnionic: sodium laurylsulfateCationic: quaternary ammoniumcompoundsBile saltsDihydroxy bile salts: Na deoxycholateTrihydroxy bile salts: Na cholateMedium-chain fatty acidsOctanoic acidDecanoic acidMedium-chain glyceridesglyceryl-1-monooctanoateglyceryl-1-monodecanoateEnaminesDL-phenylalanine ethylacetoacetateenamineMixed micellesGlyceryl monooleate + Sodium taurocholateLinoleic acid + HCO60Calcium binding agentsEDTAPhenothiazinesChlorpromazineLiposomesAzoneFatty acid derivatives ofPalmitoyl-DL-carnitinecarnitine and peptidesN-myristoyl-L-propyl-L-prolyl-glycinateSaponinsConcanavaline APhosphate and phosphonateDL-α-Glycerophosphatederivatives3-Amino-1-hydroxypropylidene-1,1-diphosphonatePolyacrylic acidDecanoic acid